Molecular control of Treg-induced effector T cell DNA damage and senescence for tumor immunotherapy

Abstract

Abstract Regulatory T cells (Treg) have a critical function for the tumor immunosuppressive microenvironments. Defining the suppressive mechanisms utilized by Treg cells is critical for the development of effective strategies to treat human cancers. However, the molecular processes that occur in responder T cells that are suppressed by Treg cells remain largely unknown. We discovered that both naturally occurring Treg and tumor-derived Treg cells induce responder naïve/effector T cell senescence with potent suppressive activity. We further identified that initiation of DNA damage is critical and the main cause for the induction of responder T cell senescence and dysfunction mediated by human Treg cells. In addition, Treg-induced effector T cell DNA damage and senescence is due to the glucose competition between Treg and responder effector T cells. Furthermore, MAPK ERK1/2 and p38 signaling functionally cooperate with the transcription factors STAT1/STAT3 to control the molecular process of responder T cell senescence induced by human Treg cells. Senescent T cells have unique phenotypes, transcriptional profiles, gene regulation signatures, and active functions, distinct from that of exhausted and anergic T cells. Importantly, our in vivo studies suggest that human Treg-induced T cell senescence can be prevented via the inhibition of DNA damage response and/or STAT signaling in T-cell adoptive transfer mouse models. These studies identify novel molecular mechanisms of human Treg suppression and provide an emerging concept that targeting Treg-induced effector T cell senescence is a new checkpoint for immunotherapy against cancer and other diseases associated with Treg cells.